Cellular regulation of hepatic bile acid transport in health and cholestasis

Anwer, Muhammad

doi:10.1002/hep.20090

Cited by 106 publications

(112 citation statements)

References 122 publications

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“…17 Up-regulation of Ntcp by insertion of Ntcp into the plasma membrane is mediated by phosphoinositide-3-kinase (PI3K) signaling pathway and protein phosphatase 2B (PP2B)-mediated dephosphorylation of Ntcp. [43][44][45] In line with this, inhibition of PI3K by wortmannin significantly decreased bile salt uptake independent of TC-or TCDC-stimulation (Figs. 6A, 7A; Supporting Fig.…”

Section: Discussionsupporting

confidence: 75%

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

et al. 2012

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The sodium taurocholate cotransporting polypeptide (Ntcp) is the major bile salt uptake transporter at the sinusoidal membrane of hepatocytes. Short-term feedback regulation of Ntcp by primary bile salts has not yet been investigated in vivo. Subcellular localization of Ntcp was analyzed in Ntcp-transfected HepG2-cells by flow cytometry and in immunofluorescence images from tissue sections by a new automated image analysis method. Net bile salt uptake was investigated in perfused rat liver by a pulse chase technique. In Flag-Ntcp-EGFP (enhanced green fluorescent protein) expressing HepG2-cells, taurochenodeoxycholate (TCDC), but not taurocholate (TC), induced endocytosis of Ntcp. TCDC, but not TC, caused significant internalization of Ntcp in perfused rat livers, as shown by an increase in intracellular Ntcp immunoreactivity, whereas Bsep distribution remained unchanged. These results correlate with functional studies. Rat livers were continuously perfused with 100 mu mol/L of TC. 25 mu mol/L of TCDC, taurodeoxycholate (TDC), tauroursodeoxycholate (TUDC), or TC were added for 30 minutes, washed out, followed by a pulse of (3)[H]-TC. TCDC, but not TDC, TUDC, or TC significantly increased the amount of (3)[H]-TC in the effluent, indicating a reduced sinusoidal net TC uptake. This effect was sensitive to chelerythrine (protein kinase C inhibitor) and cypermethrin (protein phosphatase 2B inhibitor). Phosphoinositide 3-kinase (PI3K) inhibitors had an additive effect, whereas Erk1/2 (extracellular signal activated kinase 1/2), p38MAPK, protein phosphatase 1/2A (PP1/2A), and reactive oxygen species (ROS) were not involved. Conclusion: TCDC regulates bile salt transport at the sinusoidal membrane by protein kinase C-and protein phosphatase 2B-mediated retrieval of Ntcp from the plasma membrane. During increased portal bile salt load this mechanism may adjust bile salt uptake along the acinus and protect periportal hepatocytes from harmful bile salt concentrations

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Section: Discussionsupporting

confidence: 75%

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

et al. 2012

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“…Various signaling molecules including isoforms of PKC, 7,9,13 cytosolic-free calcium (Ca 2 þ ) i , 9,25 mitogen-activated protein (MAP) kinases p38 MAPK6,12,13 and p44/42 MAPK , 11,14 src kinase 6 as well as PI3K 8,[26][27][28] have been shown to be involved in bile acid-dependent hepatobiliary exocytosis and carrier insertion/retrieval in apical membranes under various experimental conditions. 29 In the normal rat liver, TUDCA may trigger insertion of Bsep into canalicular membranes by a dual integrin-dependent signaling pathway which includes activation of p44/42 MAPK on one hand and activation of p38 MAPK on the other hand 6,[11][12][13] Preliminary evidence suggests that this pathway may be less relevant for the anticholestatic effect of TUDCA in bile acid-induced cholestasis 14,15 In TLCA-induced cholestasis, the anticholestatic effect of TUDCA appears to be mediated in part by PKC-dependent mechanisms although the exact isoform involved has not yet been determined. 7 PKCa is selectively activated by TUDCA in rat hepatocytes [30][31][32] and PKCa has been shown to phosphorylate Bsep.…”

Section: Discussionmentioning

confidence: 99%

Tauroursodeoxycholic acid inserts the bile salt export pump into canalicular membranes of cholestatic rat liver

Dombrowski

Stieger

Beuers

2006

Laboratory Investigation

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“…The expression of Ntcp is not only modulated in various pathophysiologic situations as outlined above, but its expression in the basolateral hepatocyte membrane is also subject to regulation by posttranslational modification through phosphorylation/dephosphorylation [11].…”

Section: Pathophysiologymentioning

confidence: 99%

The Role of the Sodium-Taurocholate Cotransporting Polypeptide (NTCP) and of the Bile Salt Export Pump (BSEP) in Physiology and Pathophysiology of Bile Formation

Stieger

2010

Handbook of Experimental Pharmacology

245

260

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Cellular regulation of hepatic bile acid transport in health and cholestasis

Cited by 106 publications

References 122 publications

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

Tauroursodeoxycholic acid inserts the bile salt export pump into canalicular membranes of cholestatic rat liver

The Role of the Sodium-Taurocholate Cotransporting Polypeptide (NTCP) and of the Bile Salt Export Pump (BSEP) in Physiology and Pathophysiology of Bile Formation

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